Anesthetic Effects on Thalamic Synaptic Transmission

麻醉对丘脑突触传递的影响

• 批准号: 6838793
• 负责人: PETER A GOLDSTEIN
• 金额: $ 27.64万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838793
• 关键词: GABA receptor; action potentials; anesthetics; central nervous system depressants; drug interactions; electrodes; electrophysiology; infrared microscopy; isoflurane; laboratory mouse; membrane potentials; neural inhibition; neural transmission; neurons; organ culture; sensory mechanism; thalamus; voltage /patch clamp

DESCRIPTION (provided by applicant): The mechanisms by which a diverse group of pharmacological agents produce anesthesia remain uncertain. A potentially important region within the central nervous system (CNS) for contributing to the anesthetized state is the thalamus; it is a critical relay site for sensory information, and two specific nuclei, the ventrobasal nucleus and the reticular nucleus, are considered to be essential structures in the generation of consciousness and sleep. Since anesthetics depress consciousness and induce "sleep," it is important to understand how anesthetics alter synaptic transmission and cell physiology in these two regions. Inhibitory synaptic transmission helps regulate thalamic function, and the GABA-A receptor is the primary receptor for mediating fast inhibitory synaptic transmission within the CNS. The focus of this proposal is to explore how two different anesthetic agents, the volatile anesthetic - isoflurane, and the intravenous anesthetic - propofol, modulate inhibitory synaptic transmission and neuronal activity in the ventrobasal nucleus and reticular nucleus. Aim 1 - What are the effects of propofol on synaptic transmission and membrane excitability in the thalamus? The hypothesis to be tested is that propofol will potentiate synaptic inhibition and depress neuronal activity to a greater extent in VB neurons than in RTN neurons. Aim 2 - What are the effects of isoflurane on synaptic transmission and membrane excitability in the thalamus? The hypothesis to be tested is that isoflurane will potentiate synaptic inhibition and depress neuronal activity to a greater extent in VB neurons than in RTN neurons. Aim 3 - How do propofol and isoflurane affect the ability of the RTN to regulate action potential firing in the VB? The hypothesis to be tested is that both agents will facilitate RTN-induced inhibition of action potential firing in VB neurons. By better understanding how anesthetic agents interact with specific subunits of the GABA-A receptor in different regions of the brain, it may be possible to design more selective, and therefore safer, anesthetics.

描述（由申请人提供）： 多种药物产生麻醉作用的机制仍不确定。中枢神经系统 (CNS) 中对麻醉状态有潜在重要作用的区域是丘脑；它是感觉信息的关键中继位点，两个特定的核，腹基底核和网状核，被认为是意识和睡眠产生的重要结构。由于麻醉剂会抑制意识并诱导“睡眠”，因此了解麻醉剂如何改变这两个区域的突触传递和细胞生理学非常重要。抑制性突触传递有助于调节丘脑功能，GABA-A 受体是中枢神经系统内介导快速抑制性突触传递的主要受体。该提案的重点是探索两种不同的麻醉剂（挥发性麻醉剂异氟烷和静脉麻醉剂异丙酚）如何调节腹基底核和网状核的抑制性突触传递和神经元活动。目标 1 - 异丙酚对丘脑突触传递和膜兴奋性有何影响？待检验的假设是，与 RTN 神经元相比，异丙酚会在 VB 神经元中更大程度地增强突触抑制并抑制神经元活动。目标 2 - 异氟烷对丘脑突触传递和膜兴奋性有何影响？待测试的假设是，与 RTN 神经元相比，异氟醚会在 VB 神经元中更大程度地增强突触抑制并抑制神经元活动。目标 3 - 丙泊酚和异氟醚如何影响 RTN 调节 VB 动作电位放电的能力？待测试的假设是，两种药物都会促进 RTN 诱导的 VB 神经元动作电位放电抑制。通过更好地了解麻醉剂如何与大脑不同区域的 GABA-A 受体的特定亚基相互作用，有可能设计出更具选择性、因此更安全的麻醉剂。